This project will explore a potentially novel mechanism contributing to muscle atrophy with age. Our data show that the myogenic progenitors present in muscle that are primarily responsible for postnatal muscle growth, repair and maintenance are activating an adipocyte gene program with age. This observation is particularly intriguing in that it suggests that common mechanisms may control loss of muscle mass and bone density with age, as it has been shown that adipocytes increase in the bone marrow stroma with age at the expense of osteoblast progenitors. We hypothesize that muscle atrophy and the increased fat content in muscle with age may be due, at least in part, to changes in the potential of myogenic progenitors. Aim 1 will explore myogenic progenitor potential in vivo to determine if the change in differentiation potential of the cells impacts muscle phenotype and if cell fate is affected by the muscle environment. Aim 2 will focus on the Wnt signaling pathway that negatively regulates adipocyte gene expression. Gene transfer will be used to inhibit or activate the Wnt pathway in myogenic progenitors to elucidate its role in muscle aging. In Aim 3, we will determine if the changes in myogenic progenitor potential with age observed in mice also occurs in humans. Progenitors will be isolated from muscle of aged and young volunteers who have been physiologically and functionally characterized, and their differentiation potential assessed. Finally, in Aim 4, gene expression in myogenic progenitors and bone marrow stromal cells from both humans and mice will be examined using microarray technology to identify patterns of expression characteristic of mesenchymal progenitor cells in adult tissues. We will identify changes in gene expression that are indicative of a change in potential with age. In summary, changes in mesenchymal progenitor cell fate will be characterized and their contribution to the decline in the musculoskeletal system established. Putative regulators of the change in fate will be identified and future studies will evaluate their potential as targets for therapeutic intervention to prevent, slow, or even reverse the loss in the musculoskeletal system with age.